Production of lysine and intermediates



Patented Aug. 15, 1950 PRODUCTION OF LYSINE AND IN TERMEDIATES Alexander Galat, Yonkers, N. Y.

N Drawing.

Claims.

I My invention relates to an improved process for the manufacture of a,e-diaminocaproic acid, or lysine, and to certainintermediates obtained in the course of such manufacture.

Lysine is an indispensable constituent of food, being necessary for the maintenance of health and proper assimilation of. other food substances by'the animal organism, and is classified as one of the essential amino-acids. However, many natural proteins, for instance, gliadin, zein, etc., are very .poor in thisamino-acid; hence, where the protein component of the diet consists in large part of gliadin, zein and the. like, it must be either supplemented by other protein rich in lysine, or reinforced by the addition of lysine itself.

Both the isolation of lysine from proteins and its synthesis have untilrnow been exceedingly costly, so that the reinforcement of foods with this amino-acid was, as a general proposition, quite out of the question, particularly in the diet of agricultural animals.

It isaccordingly the general obi ct of the present invention to provide aprocess forthe syn thesis of dl-lysine, whereby such acid can Joe obtained at such low cost as to make it practical to useit for the supplementation even of animal foods. a

More specifically,it is an object of the invention to provide a simple and efficient process for the manufacture of dl-lysine from e-aminocaproic acid; or from derivatives of such monoamino acid which can readilybeconverted thereinto, such as ecaprolactam. T

Other objects and advantages of the invention willappear from the following detailed descriptionof the invention.

dl-Lysine has already been synthesized by a variety of methods but they all sufiered from one or more if the disadvantages of being lengthy, tedious, low in yield, or expensive by reason of the employment of special materials which are not commonly available. See Berichte 35, 3772,

"1902; Compt. rend. trav. lab., Carlsbad, 6, 1, 1903;

J. Chem. Soc. 1939, 1564; J. Pharm. Soc. Japan, 550, 1044, 1927. l

ck and Marvel (Organic Syntheses, Coll. vol. 2) have modified an earlier synthesis by von Braun (Ber. 42,839, 1909), and used e-caprolac tam as the starting material. This was converted into e-benzoylaminocapr-oic acid, which was then brominated with phosphorus and bromine, thereby ultimately yielding e-bEl'lZOYliLIIlinO-w-blOHIO- caproic acid. Thisintermediate'was then ammonolyzed with aqueous ammonia. and finally.

Application November 15, 1946, Serial No. 710,216

Both the Eek-Marvel and Von Braun syntheses are, however, very difficult to perform, and their yields are not satisfactory. Even on a laboratory scale the bromination step causes very great difficulty, which is increased when reasonably largescale operations are attempted.- Extremely great care must be exercized during the treatment with phosphorus and bromine, and when fairly large quantities are worked with, it becomes practically impossible to prevent such large losses as to make the process uneconomical. This is due largely to the fact that the reaction between phosphorus, bromine, and e-benzoylaminocaproic acid is very exothermic. In order to avoid decomposition and charring, effective cooling and stirring are essential.v However, the reaction mixture has the consistency of a heavy tar, making efficient stirring and abstraction of heat almost impossible. The use of diluents is extremely detrimental to the yield, the latter decreasing by as much as 50 per cent if dilution is attempted (Organic Syntheses, vol. 2, page 75, Note 1). Because of these circumstances the yield obtained by the bromination step is very erratic and may vary by as much as 30 per cent from one run to another even on a laboratory scale. As the scaleof the runs is increased, the yield decreases correspondingly, since the factors of exothermicity, stirring, and removal of heat become progressively more critical and more difficult to control. In addition to these disadvantages, theknown methods required the use of considerable amounts of the relatively expensive phosphorus and bromine.

I have found that e-acylaminocaproic acids may be (at-halogenated rapidly, simply and economically by the use of sulfuryl halides, and particularly the chloride, as the halogenating agent. The suliuryl halides are readily available and are relatively inexpensive. That these reagents would halogenate thee-carbon of e-acylaminocaproic acid was, however, quite unexpected in view of the fact that the starting compounds contained two points which are vulnerable to attack by the reagent; namely, the amido group and the a-hydrogen. It is well known, and it has been my experience also, that the amide group is by far more reactive than the a-hydrogen, and should therefore be preferentially attacked. Thus I have found that when benzoylamino acetic acid, CsI-IsCONHCHzCOOI-I is reacted with excess sulfuryl chloride in the presence of a small amount of a catalyst, such t K a) "as iodine, there is obtained a chlorinated compound which contains chlorine in the amido group but none in the a-DOSitiOn. Again when benzoyl amino propionic acid,

CeI-IeCONH (CI-I2) zCOOl-I is reacted with excess sulfuryl chloride and a catalyst, there is obtained a chlorinated compound which contains chlorine in the amido gtoup but none attached to the a-carbon.

It was therefore surprising to discover that when ebenzoylaminocaproic acid,

CGH5CONH(CH2) 5000a was treated in exactly the same manner as the: acetic, propionio and butyric acid compounds, the

chlorine atom became attached to the 'e-carhon and the a-ChlOIO acid was obtained in yields crdseto one hundred per cent of the theory.

I have found further 'that, in contrast to the reaction with-phosphorus and bromine, the eacylaminoc aproic acid react with sulfur'yl halides smoothly, non-exothermically, and at moderate temperatures, and form clear, homogeneous solutionswhich need not be stirred or cooled. -Also, in contrast to the reaction with phosphorusand bromine, I; obtain with suliurylhalides consistent and reproducible yields which do not vary materiallyqfromone run to another, and are practically independent of the scale of such runs.

, ployed, I prefer toprotect the amino group with a. benzoyl radical because the newintermediate which I obtain by the-subsequent treatment with sulfuryl chloride-has more advantageous solubil-ity characteristics-and may --.be more readily isolated. The acylaminocaproio acid is -:then mixed with the sulfuryl halide, there being added a smallamount of a'catalystsuch as iodine. I preferto use sulfuryhchloride since it is inexpensive and readilyavailablea The mixture-is heated on the waterbath "until the evolution of gas slackens, which usually =occurs-after several hours.- .I then remove the -excess sulfuryl halide by distillationtreat the residue with water,- colleot the precipitated chloro 'acid, and wash and dry it.

I then-ammonolyze the e-acyla'mino a-halogenocaproic acid, by one of the methods known to the art, as with concentrated aqueous or alcoholic ammonia, either at room temperature orby heating under pressure. I may also use a mixture of amrn'oniaan-d ammonium salt, such as ammoniumcarbonate. When-ther'eaction is complete,

'I remove the excess ammonia, whereupon e-aoyl amino a aminocaproicaci'd crystallizes out. This is filtered off and can be converted intodl-lysine by hydrolysis in'known manner. 1

The following example illustrates a satisfactory procedure embodying the present invention,"but it will be understoodthat the same is presented solely for purposes of illustration and not as indicating the limits or scope of the invention:

EXAMPLE (a) e-Benzoylaminocaproic acid e-Caprolactam 67.8 g. (0.6 mole) NaOI-I 48.0 g. (1.2 moles) Water 300.0 cc.

The above materials were refluxed for 30 minutes in a 1 liter three-neck flask, pumice being added to regulate the boiling. The solution was then cooled to 15 C. (ice bath) and there were added dropwise and with vigorous stirring and eooling 71 cc. (86.5 g.0.62 mole) of benzoyl chloride. During the addition the temperature was kept at about 19 to 23 C., the bath being kept at about 13 to 15 C. The time of addition was one and one-hail hours and the mixture was additionally stirred for 15 minutes. The reaction mixture was then diluted to "150000. with water and dilute HCl (1:1) was added with stirring. The addition of H61 must be slow at the beginning and seeds mus-t be added to the mixture, as otherwise the acid may precipitate in an oily condition. Altogether, 120 cc..of HCl (1: were added, the temperature being kept at about 15 C; The mixture was allowed to stand for about two and one-half hours at this temperature, the benzoylate'd aminocaproic acidwas filtered off, washed free from chlorine, and dried. Theacid can be dried at room temperature with or without vacuum 'or in the oven at 40 to In this manner the acid was obtained as a fine 'crystalline powder. -If the drying is carried out at or above, theacid' m'elts. It can then be dried in the molten condition, "cooled and powdered. Yield: 132 g. (93.5%). M. P. 75 to 78 C.

(b) e-Benzoylamino-achlorocai roic acid e-Benzoylaminocaproic The acidand iodine were powdered and mixed with the SO2C12 in a 300 cc. ground-joint flask. On shaking for about gt); minutes a homogeneous solution was formed. y The flask waswarmed on a water bath, using a long reflux condenser conneoted to a trap. The reaction mixture sometimessepa-rated into two layers and during the reaction the upper layer increased 'in volume at the expense of the lower layer. .Thebath was kept atoll to 65 C. 'forabout oneand one-quarter hours, when evolution of gas sloweddown. Duringthe next one and one-half "hours the temperature was-slowly raised to the boiling point. At-t-his point the evolution of gas almost ceased and the sulfuryl chloride no longer refluxed, the excess having been-driven'ofi by theI-ICl and S02 during thereacti'on.

120 "cc. of water (room temperature) were added tothe-hot reaction'mixture and the fiask was shaken by hand. Reaction with the water took placeand finally a red-oil sank to the bottom. Shaking of the flask was continued until the 'red oil became a light yellow. The contents were then poured'intoa 400 cc. beaker and the hot aqueous layer was used to rinse the flask to remove the oil adhering to the walls. The water'was'finally-decanted and the oilwasshaken with '120ccwof water-atsBO to C.-(coldwater is not quite 'as suitable). The oil was shaken 5. with the hot water until it become solid, which required about 10 minutes. The water was then decanted from the crude, yellowish chloro-acid. Yield of the wet crude material: 44.4 g.

The wet crude acid can be used directly in the next step. For the purpose of calculating the yield a portion was air dried. The yield of dry, crude, chloro acid was 38.7 to 39.32 g. (96 to 97.5%). M. P. 115 to 125, which rose to 145 to 147 after recrystallization.

An additional small amount of chloro acid crystallized from the hot mother liquors used for the washing of the crude acid.

() e-Beneoyl-dl-lysine 2.5 g. of the crude wet chloro-acid were dissolved in 40 cc, of concentrated aqueous ammonia and the solution was heated in a pressure bottle for 7% hours at 85 to 90. On cooling,

the mixture was transferred into a 300 cc. dis tilling flask and evaporated under vacuum on a boiling water bath almost to dryness. During the evaporation, the benzoyl-lysine crystallizes out. The residue was taken up in a small amount of water, cooled, filtered, washed with a little water, and then with about 15 cc. of methanol and dried at 80 to 90.

Yield: 1.2743 g, (60%, based on e-bBIlZOYlaminocaproic acid) M. P. 265 to 270.

(d) all-Lysine 12.5 g. of e-benzoyl-lysine were refluxed for 10 hours with 76.5 cc. of concentrated HCl and 50 cc. water. The mixture was then evaporated to dryness in vacuo on a water bath. 80 cc. of denatured 95% alcohol were added and the mixture refluxed until the solid material dissolved. The solution was transferred into a 250 cc. beaker and a solotion of g. of pyridine in cc. of alcohol was added. The mixture was allowed to stand over night, after which the precipitated dl-lysine hydrochloride was filtered off, washed with cc. alcohol and dried at about 80.

Yield: 8.02 g. (88.5%). M. P, 260 with decomposition.

The purification of the crude dl-lysine hydrochloride was carried out as follows: 5 g. of the crude material were dissolved in 15 cc. of water, the solution was charcoaled hot, filtered, washed with 5 cc. of boiling water and 80 cc. of denatured 95% alcohol added. The mixture was allowed to stand over night, after which the mother liquor was decanted and the crystals stirred with a mixture of 49 cc. of alcohol and 7 cc. of water. The crystals were then filtered off and dried in vacuo.

I claim:

1. The process which comprises heating and reacting e-benzolyamino caproic acid with sulfuryl chloride in the presence of a catalytic amount of iodine until the a-ChlOIO acid is formed, heating the product with ammonia to form the benzoylamino-a-amino acid, and heating the latter with a hydrolyzing agent to free the e-amino roup.

2. The process which comprises heating and reacting e-benzoylamino caproic acid with sulfuryl chloride in the presence of a, catalytic amount of iodine until the a-ChlOI'O acid is formed.

3. The process which comprises heating and reacting e-benzoylamino caproic acid with sulfuryl chloride until the a-ChlOlO acid is formed.

4. Process for the manufacture of dl-lysine which comprises heating e-benzoylamino caproic acid with a sulfuryl halide, heating the a-halogen acid so formed with ammonia to form the corresponding a-amino acid, and heating the product with a hydrolyzing agent to free the e-amino group.

5. Process according to claim 4 wherein the sulfuryl halide is the chloride.

- ALEXANDER GALllT.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,302,228 Kharasch et al. Nov. 17, 1942 FOREIGN PATENTS Number Country Date 157,816 Germany Jan. 18, 1905 OTHER REFERENCES Lassar-Cohn: Arbeitsmethoden fiir Organisch-Chem. Lab., 4th Edit, Special Part (1907) p. 385 and pp. 452 to 456.

Braun: Ber. Deut. Chem, vol. 42 (1909), pp. 842-845.

Eck et al.: J. Biol. Chem, vol, 106 (1934), pp. 388-391. 

3. THE PROCESS WHICH COMPRISES HEATING AND REACTING E-BENZOYLAMINO CAPROIC ACID WITH SULFURYL CHLORIDE UNTIL THE A-CHLORO ACID IS FORMED. 